Water-soluble derivatives of 2-methyl-1, 4-dihydroxy-naphthalene and processes for their production



Patented Sept. 30, 1947 f WATER-SOLUBLE DRIvATivEs oF V2- METHYL 1,4-DIHYDRoXY-NAPHTHA- LENE AND PROCESSES PRODUCTION Y.

.'FOR THEIR I l.llritz von Werder, Darmstadt, Germany; vested in the' Attorney Y* General of the United States No Drawing. "Application February 6,1941, Serial No. 377,673. Germany March 23, 1940 1 invention relates to' water-soluble derivatives of 2methyl1,4-dihydroxyfnaphthalene and processes for their production.v Y'

-v Compounds which are derived from Z-methyl- 1\,.1.Anaphthoquinonel have lately metv with particular interest 4because this quinone displays approximately the same, possibly an even greater antihemorrhagic activity Aas the natural coagulation vitamin K1. For thetherapy offvitamin Kw deficiency diseases in Whichresorption disturbiancesplay a decisive role, active agents for parenteral and, in particular, intravenous -adminf istration are preferred.V Water-soluble` deriva,-

tives of Z-methyl-lflfnaphthoquinone-with Vita.

ming- K action, therefore, -meritgspecial interest. A-n 1 1mber of Water-solublev compounds of this series have alreadyV been proposed for -use in the vitamin K therapy. Almquist and Klose [J ournal of the American Chemical Societyfvolume 61',v page 1923 (1939)] considered,v the coloring matphthiocol (2-methyl-S-hydroxyflA-naphthoqui# none) suitable, but Fernholz and Ansbacher [Science 9 0, 2331, p. 215 (1939)] Were able to proVexthat a-s acoagulation vitamin, phthiocoliis gested` 1,41dihydroxy-Z-methyl-naphthalene and 1,fl-dihydroxy-2-methylelfaminonaphthalene for thepurpose in question. However, Fieser andi Fjryl'LJournal ofthe American Chemical Society, I

vo l.- 6 2; Dp. 228- 229(1940)] rightfully pointed ,f onlyweaklyactive.; Doisy and cao-Workers "[compare, for examplaournal of the AmericanvChemf ical Society, vol. 61, p. 2563 (1939)] have sug out that 2-,methyl-1,1i-naphthohydroquinone,and

aminonaphthol derivatives are extremelt7 susceptibleto oxidation.- They are, therefore, not suflciently stable for the practical application as. medicinal remedies. Moreoven as my own experiments have shown, lthese compounds are usually not well tolerated. Fieser and Ery (loc. cit.) have decided-,upon an interesting procedure, by preparingv thev Water-soluble alkali salts of sulfurie and phosphoric acid esters of 1,l=dihydroxyv 2-mthyl-naphthalene. But even these preparations f stillj show allnumber of imperfections. The sodium-2-methyl-Alflnaphthohydroluinone.t

disulfate is not very Water-soluble,` as it can be recrystallized from water. For the clinical experiment described yin" the. publication by Fieser and'Fry, the salt-Was used only in a 0.1% solution. vThe yields, too, are unsatisfactory; accordin'g`to the statements by Feser a `nd Fr y2 only about"42% of theoryycalculated'on the 1,4- dihydroxy-,2i4methyl-naphthalenel used, of still impure dium salt of the phosphoric acid ester, on the biologic activity of which Foster, Lee and Solmssen, Journal of the American Chemical Society, vol. 62, p. 453 (1940),-also reported briefly, is ex- V4tremely hygroscopic and deliquesces in the air.

The present invention opens up a new class of water-soluble derivatives of lA-dihydroxy-Z- methyl-naphthalene with vitamin K action. The

new compounds are crystalline substances, easily 10 soluble in Water, stable, and not sensitive to light and air. they possess the advantage of being non-hydroscopic, Yand of making Y possible control of their degree of purity through the melting point.

According to my invention, easily Water-soluble derivatives of Z-methyl-1,4-dihydroXy-naphthalene are prepared by esterifying 1,4-dihydroXy-2- methyl-naphthalene with such organic acids as contain a nitrogen atom capable of salt formation. Thev nitrogen atom can be present in an aliphatic or in a cycliclinkage; Esterication is preferably effected by Warming 1,4-dihydroXy-2- methyl-naphthalene with the corresponding amino acid chlorides or their hydrochlorides, re-

spectively,-with or Without Vagents for binding hydrogen chloride.

Another method is that of first preparing the halogen fatty alcid esters of 1,4i-dihydroXy-2- methyl-naphthalene, hitherto not 'described in the literature, and then reacting these 'with amines. y y;

In the treatment with an excess of amine, partial saponication may occur; monoesters are obtained,fand' their vsalts are likewisejeasily soluble in water. V'l'.lfle basic esters arewconverted into'Water-soluble salts in the usual'manner, for exampleQb-y treatment inr an ether solution with ethereal hydrochloric acid. y

4The above describedfproceclure can, of course,

'also' readily be carried outwith the derivatives of 1,4-dihydroxy-naphthalene, substituted in the 2-and/.or inthe 3'postionby saturated or unsaturated lhydrocarbon residues which, per se or in the form of quinones, show antihemorrhagic activity.

The' following examples 'are presented by Way of illustration and not of limitation, for obviously, certainy modifications in the steps of the process and the quantities of the materials employed may rr'barriade Without f departing from the spirit vand scope of the disclosures' herein.

Examples methy1 hexahy'dronicoumc acid) is heated with In addition to being very water-soluble,

800 cc. of thionyl chloride and refluxed for two hours, The excess thionyl chloride is distilled oil in vacuo, the residue is triturated with petroleum ether, suction-ltered, washed with petroleum ether and dried. The crude N-methylnipecotic acid chloride hydrochloride with a melting point of 159 issuilciently pure for further working up procedure. The yield is 93.5% of theory.

8.5 g. of 1,4-dihydroxy-Z-methylenaphthalene and 24 g. of N-methyl-nipecoticacidchloridehyfdrochloride are triturated thoroughly and: heat ed slowly in a nitrogen atmosphere. The temperature is maintained at 11G-140 for three, hours. After cooling, the reaction mixture isdissolved in 85 cc. of 5% hydrochloric acid; The ester base is precipitated theaddition, oi; exe cess 10% sodium hydroxide solution, Afterxprq... longed standing, the initially oily precipitate becomes solid; it is filtered, Washed with Water, and dried. 'Ihe yield is21 g. equal to 86.4% of theory. The material isdissolved in absolute etherA and treated with ethereal'. hydrochloric acid. The hydrochlorideisltered, washed with etherfandrecrystallized from. alcoholin the presenceof!charcoal'.` The: hydrochloride of 1,4'di hydroxy-Z-methylenaphthaleneebis (N=methyl n-ipecotic acid)` ester formscolorless crystalsV which melt at 2859 and Whose analytical' values cor-respond tothe empiricalv formula C25H34O4N2C12. The salt Vis readily soluble in water. The aqueous solution is stable to light'r and airand can be sterilized.

The isethion-ic acidvsalt and the lacticacid'salt of the above-mentionedl base are particularlyleneare trituratedv With- 40g. of chloracetic acid' anhydride and heated" for- 4 hours at 1109 in a nitrogen atmosphere. After cooling, the solidied melt is dissolved in warm etherrIfhe solution is stirred for tWo hours with an equal-volume of Water. The precipitated Chlor-acetate is liltered and Washedwith ether. The ether solution is separated from. the filtrate, washed with 0.5- N; sodium bicarbonate solution4v and with Water, dried, filtered, concentrated, andinally dried in vacuo. Theresidue, together With` thepreviously separated portions, is recrystallized from 90% alcohol. The 1,4-dihydroxy-2-Inethyler1aphtha` Iene-dichloracetate formscolorless leaets Witha melting point of 111. The yield is 27.2 g., corresponding to-85% ofv theory;

20 g. of 1,4-dihydroxy-2-methylenaph'thalene-dichloracetateare reluxed with 200 cc. of'

diethylamine in a hydrogen atmosphere forY 3 hours on a bath at 70. The diethylamine hydrochloride crystallized outl is filtered, WashedV with ether, and dried. The yield is 97% of theory. The iiltrate is evaporated in vacuo to drynessrand the residue triturated with normal benzine. The undissolved portion is freed in vacuo from residual benzine and dissolved in 400 c c. of 5% hydrochloric acid. The ester base is precipitated by an addition of %y sodium hydroxide solution. The oily material is taken up inether, the ether'solution Washed with Water, dried over ignited'poe tassium carbonate, concentrated, and treated with eth'ereal hydrochloric acid. rIv'he hydrochloride of- 1,4-dihydroxy- 2 methyl-naphthalene-l-diethylamino acetic ester is filtered andrecrystallized from alcohol-in the presence orcharcoal. The easily watersoluble crystals melt at 248.

(3) 53cc. off anhydrous pyridine are heated with passage of hydrogen, and recooled. In this solvent is dissolved 5.3 g. of 1,4-dih'ydroxy-2- methyl-naphthalene, to which is then added 9.3 g. of nicotinic acid chloride. The reaction mixture, which has become warm, is allowed to stand in a closed vessel. After 20hours the pyridine is distilled-V oir in high vacuo and' the residue dissolved in 53 cc. of 5% hydrochloric acid.

The ester base precipitated by an addition of 10%;SQdium0hydroxide solution is filtered, washed Withwater andrecrystallized from acetone in the presencceof charcoal. The 1,4 dihydroxy 2 metnyl'g-naphthalene-bis (nicotinic acid) ester crystallizes from acetone in coarse granules which melt" at 1158"-1'69".4 The yield is 10 g., equal to 85.5% of theory. For the preparation of th'e hydrochloric acidisaltthe ester base is dissolved in absolute'. alcohol; and treated with alcoholic hydrochloric. acid. The hydrochloride melts at 25th-260;

(4) 5.8 g. of 1,4 dihydroxy 2,3 dimethylnaphthalene and 153 g; o'NLmethyllnipecotic acid chloride-hydrochloride` are triturated1 thoroughly and heated for 4 hoursat 140 ina nitrogenl atmosphere. After cooling, the materia-lis digested solution. and-i recrystallized` from a small'y amount,

from undissolved portions; The undissolved ma'- teria-l` isv Washedx with 50 cc: of 5% hydrochloric acidi andi 15'0 cc. ofi water. Filtrate andwashings are combinedlandmadedistinctlyalkaline by thel addition of` 40% 'sodav solutioni The baseprecipitatedlin: granules issuction-ltered and taken` up in ether,V tha ethereazll solution washed withwater, dried.' over. potash,1 iilteredl, and concen trated to a,Y volumecff 2001cc; Bythe' addition- 0i ethereal hydrochloric( acidl the:4 hydrochloride is'- precipitated; which, after standing for a shorttime, is suctionaflt'ered;Washediwith ether, anddried: Yield 8;9:g=. Thefsalt isadissolved. in: water, the. basez liberatedl by; the1 additionN off soda.

of` acetoneor cyclohexane. 'I-'he-1,4'-d.ihydroXy- 2,3fdimethylnaphthaleneebis -NNI -methylf nipecoti'c acid= ester cryst'allizes` fromI acetone and' cyclohexane,` respectively; im coarse aggregates;

meltingat .15,lffand?yieldingA analytical-values cors-- drochlorideofftheesterisaoolour-lesslpowder andV melts` at 301 to 3029s I (5) 332g. of! 134'-dhydroxy-T-methylenaphtha- Iene are dissolvedin-132fcc ofdryvpyr-ldineandA treatedwithv g. ofiNfpiperidinoacetylchloride hydrochloride with constant stirring (cti DRP. 629,0529-y thenmixture War-mingjto 751-8091with in'- itialfclariication; By-h'eat supply` the whole is` maintained' for another hour; at 80- with` stirring; then-cautiouslytreated' withl 800 cc: ofi-5 hydrochloric'acid,`A by coolingwith ice water; After-theaddition of'1\l'; ofwater, 1750gcc; of'` 40%' soda' solution-are'added andthefbaseprecpitated as-anV oilf istaken up, in* ether: The ethereal solution Washed: with` Water is driedE overepotash, ltered; concentrated to avolumeof' 2:5112 andtreatedwitn 300 cc: ofeth'erealhydrochloric acid. Thepre'- cipitatedhydrochlorideis suction-f-lteredvat once, Washedg' with; absolute ether, and treatedA with 250 ce; of'al'coholf inn thewarm. After. standing; for 6 hours, there are addedy afurther 250 cc. `of-cold alcohol the puried saltis suction-filtered;V washed with alcoholandetlfien anddrlediA Yield' 58- g.; melting'- point` 262.y The` l'ifl-dihydroxy-2`4 methyl-naphthalenebis f N piperidine*l acetate prepared' from this lnateriagljY forms colourless crystals ffrom-,et-hei, ,l melts at 10E-106i'i andlyields C25H3z04N2. The absorption spectrum in the ultra. violet shows a maximum at the Wave-length of 283 m/r, the extinction coefficient El tZ111. 5

being 195 at this Wave-length. The hydrochloride prepared from the crystallized base melts at 264.

(6) 47 g. of 1,4-dihydroxy-2methylnaphtha lene are dissolved in 188 cc. of pyridine and treated with 191 g. of a-diethyl--dimethylamino-propionic acid chloride-hydrochloride (cf. DRP. 629,054), the temperature rising up to about 70. The mixture is stirred for an hour at 80, taken up in hydrochloric acid after cooling, and, for precipitation of the base, treated with soda solution, and extracted with ether. The crude hydrochloride precipitated from the Washed, dried and concentrated ethereal solution is treated with acetone and again converted into the base, which is now recrystallized from petrol ether in magnicent, colourless crystals. The 1,4 dihydroxy 2-methyl-naphthalene-bis--diethyl--dimethylamino-propionate melts at 79 and yields analytical values corresponding to the formula C29II44O4N2- The hydrochloride melts at 230, its aqueous solution has an absorption spectrum which is characterized by a maximum at 1 283 mp E1 C .-172

and a minimum at CHS l CH3 55 1,4 dihydroxy 2-methyl-naphthalene-bis-(nicotinic acid) ester having the formula and 1,4 mhydroxy 2 methyl-naphthalene-bs- 70 piperidine acetate having the formula GHz-CH:

CH2-OH:

2. 1,4-dihydroxy-2-methy1 naphthalene bisv (N-methyl-nipecotic acid) ester having the CHI \N 4. 1,4-dihydroxy-2-methyl-naphthalene-bis-N- piperidino acetate having the formula CH2-CH,

CHa

CH2-CH2 FRITZ VON WERDER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 1,984,511 Anderson et a1. Dec. 18, 1934 2,138,809 Reiff Nov. 29, 1938 2,372,655 Bochmuhl Apr. 3, 1945 OTHER REFERENCES J. American Chemical Soc., vol. 61 (1939), p. 2561.

J. AmericanChemcal Soc., vol. 62 (Jan. 1940), pp. 228-9.

J. American Chemical Soc., vol. 62 (Jan. 1940) pp. 153-158. 

